Characterization of dsRNA-induced pancreatitis model reveals the regulatory role of IFN regulatory factor 2 (Irf2) in trypsinogen5 gene transcription
Abstract
Mice deficient for interferon regulatory factor (Irf)2 (Irf2-/- mice) exhibit immunological abnormalities and cannot survive lymphocytic choriomeningitis virus infection. The pancreas of these animals is highly inflamed, a phenotype replicated by treatment with poly(I:C), a synthetic double-stranded RNA. Trypsinogen5 mRNA was constitutively up-regulated about 1,000-fold in Irf2-/- mice compared with controls as assessed by quantitative RT-PCR. Further knockout of IFNα/β receptor 1(Ifnar1) abolished poly(I:C)-induced pancreatitis but had no effect on the constitutive up-regulation of trypsinogen5 gene, indicating crucial type I IFN signaling to elicit the inflammation. Analysis of Ifnar1-/- mice confirmed type I IFN-dependent transcriptional activation of dsRNA-sensing pattern recognition receptor genes MDA5, RIG-I, and TLR3, which induced poly(I:C)-dependent cell death in acinar cells in the absence of IRF2. We speculate that Trypsin5, the trypsinogen5 gene product, leaking from dead acinar cells triggers a chain reaction leading to lethal pancreatitis in Irf2-/- mice because it is resistant to a major endogenous trypsin inhibitor, Spink3.
- Publication:
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Proceedings of the National Academy of Science
- Pub Date:
- November 2011
- DOI:
- 10.1073/pnas.1116273108
- Bibcode:
- 2011PNAS..10818766H